An effective retinal prosthesis would improve the lives of hundreds of thousands or millions of blind patients, depending on its effectiveness. This has been the goal of many research teams over the past two-decades. Prostheses based on electrical stimulation of the retina are being developed and tested in sighted animal models, and have been acutely tested in patients, but have had limited success to date. Major problems associated with electrical stimulation include the wide spatial spread of current at levels which are required to stimulate degenerated retinal tissues and degradation of metal electrodes by stimulation voltages that often exceed those required to dissociate water. This poses a serious risk of device failure and retinal tissue damage from free radicals that are toxic to the lipid membranes of neurons and glia. These problems are more common in the small-diameter electrodes required for a high-resolution prosthesis. In addition, current technology cannot selectively stimulate specific types of visual pathways (e.g. ON and OFF channels) within the visual system via electrical stimulation. Thus, electricity cannot encode important sensory features used in normal central visual processing. Many of these limitations could be overcome or reduced by using more naturalistic means of eliciting retinal ganglion cell (RGC) firing. Natural vision is encoded as neurotransmitter signals. The proposed research will enable us to design and build a retinal prosthesis based upon the physiological requirements for RGC stimulation to exogenous neurotransmitter stimulation in two animal models with retinal degeneration. Recordings in retinal whole-mount preparations will be used to determine the parameters for RGC stimulation using neurotransmitters. We will measure the concentration and volume of drug delivery required to effect RGC firing, the types and effects of potential neurotransmitter candidates (glutamate, glycine, GABA and acetylcholine), the spatial characteristics of drug stimulation, the dynamic range (i.e. the duration and magnitude of stimulation), and the temporal resolution of repetitive stimulation. It is important to define these parameters for retinas, which have undergone degenerative changes similar to the eyes of intended patient recipients of devices. Therefore, these parameters will be collected from two animal models of retinitis pigmentosa, at major stages of degeneration. We have initiated the design of a microfluidic neurotransmitter-based retinal prosthesis, and will modify our existing platforms to test our prototype devices in-vitro. Our device is a flexible thinfilm epiretinal microfluidic stimulator with arrays of rounded polymer microneedles facing the ganglion cells. The dimensions of the array spacing, height and pore size of microneedles will be modified according to the physiological responses of RGC tests in-vitro using healthy and degenerated retinal wholemounts. We will characterize neurotransmitter release via pneumatic and electroosmotic ejection methods. Our long-term goal is to test these devices, in-vivo.